2023 journal article

Efficacy of an isoxazole-3-carboxamide analog of pleconaril in mouse models of Enterovirus-D68 and Coxsackie B5


By: T. Lane*, J. Fu*, B. Sherry n, B. Tarbet*, B. Hurst*, O. Riabova, E. Kazakova, A. Egorova ...

co-author countries: Russian Federation 🇷🇺 United States of America 🇺🇸
author keywords: Antiviral; Coxsackievirus B5; Cryo-electron microscopy; Enteroviruses; EV-D68
MeSH headings : Animals; Mice; Enterovirus D, Human; Isoxazoles / pharmacology; Isoxazoles / therapeutic use; Cryoelectron Microscopy; Enterovirus Infections / drug therapy; Enterovirus; Antiviral Agents / pharmacology; Antiviral Agents / therapeutic use; Hand, Foot and Mouth Disease / drug therapy; Enterovirus B, Human
Source: Web Of Science
Added: July 24, 2023

Enteroviruses (EV) cause a number of life-threatening infectious diseases. EV-D68 is known to cause respiratory illness in children that can lead to acute flaccid myelitis. Coxsackievirus B5 (CVB5) is commonly associated with hand-foot-mouth disease. There is no antiviral treatment available for either. We have developed an isoxazole-3-carboxamide analog of pleconaril (11526092) which displayed potent inhibition of EV-D68 (IC50 58 nM) as well as other enteroviruses including the pleconaril-resistant Coxsackievirus B3-Woodruff (IC50 6–20 nM) and CVB5 (EC50 1 nM). Cryo-electron microscopy structures of EV-D68 in complex with 11526092 and pleconaril demonstrate destabilization of the EV-D68 MO strain VP1 loop, and a strain-dependent effect. A mouse respiratory model of EV-D68 infection, showed 3-log decreased viremia, favorable cytokine response, as well as statistically significant 1-log reduction in lung titer reduction at day 5 after treatment with 11526092. An acute flaccid myelitis neurological infection model did not show efficacy. 11526092 was tested in a mouse model of CVB5 infection and showed a 4-log TCID50 reduction in the pancreas. In summary, 11526092 represents a potent in vitro inhibitor of EV with in vivo efficacy in EV-D68 and CVB5 animal models suggesting it is worthy of further evaluation as a potential broad-spectrum antiviral therapeutic against EV.